The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in solid organ transplant patients poses a considerable challenge due to the underlying immunosuppression which inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. Preliminary studies developed in our laboratory suggest that it may be possible to overcome this inherent problem using a novel protocol to activate autologous EBV-specific CTL lines from these patients and to show for the first time their potential use for immunotherapy against PTLD in solid organ transplant patients. To establish the clinical use of this protocol, we propose to conduct a phase I/II clinical trial in a cohort of solid organ transplant patients with PTLD. To achieve this, we have drawn together scientific expertise within the EBV Unit at QIMR and major transplant units in Australia. In the first instances, we propose to further refine the in vitro conditions for activating EBV-specific CTL from solid organ transplant patients who are on high levels of immunosuppression. Two absolute requirements have been set: (1) EBV specificity at the CTL peptide epitope level; and (2) complete lack of anti-donor alloreactivity which would threaten the integrity of the transplanted graft. Having defined these conditions, we propose to conduct a phase I/II trial by adoptively transferring autologous EBV-specific CTL into solid organ heart, lung, and heart/lung transplant patients with PTLD. As far as we are aware, this represents the first such trial to be conducted and seeks to (1) determine the safety of adoptively transferring EBV-specific CTL into solid organ transplant patients; (2) determine the longevity of these CTL in vivo using a genetic marker; and (3) determine the extent of clinical regression of PTLD.